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Trial design and outcomes for inherited neuropathy studies
D. Pareyson
IRCCS Foundation C.Besta Neurological Institute
Milan, Italy
MSG Meeting, Buffalo, NY
September 22, 2009
Disclosures
• No conflict of interest
• Conducting a trial of ascorbic acid in CMT1A funded by Telethon-Italy and AIFA (Italian Medicines Agency)
• No honorary from any company
• Travel grants + meeting participation from Kedrion
• Highly heterogeneous, different pathogenic mechanisms
• Slowly progressive disease• Variability in disease
severity and course • Some forms very rare
Need • Natural history studies • Long study duration, large
samples of pts. • Multicenter studies• Reliable and responsive OM
Charcot-Marie-Tooth 1A (CMT1A)
• Most frequent CMT type (40-50% all CMT)
• Animal models available
• Down-regulation of PMP22 expression
• Progesteron antagonists, Neurotrophin-3 (NT3), ascorbic acid beneficial in animal models
• Opened clinical trial phase
France, 180 patients placebo, 1 gram, 3 grams,1 year - CMTNS
Holland, 12 patients 12-25 yrs, MCV
Italy-UK, 272 patients placebo, 1.5 grams2 years - CMTNS
Germany, 50 childrenplacebo, 3 grams
Czech Rep. 60 patientsplacebo, 1.5 gr - CMTNS
US, 120 patients Placebo, 4 grams2 years - CMTNS
Australia, 81 children, 1 year
Clinical OM used in CMT• Impairment
– Strength assessment: MRC, myometers
– Sensory assessment: INCAT sensory sum score (ISS), Semmes-Weinstein monofilaments
– Composite: CMTNS, NIS
– VAS for pain, fatigue, cramps, etc.
• Disability
– Walking: 10 meter timed walking, Ambulation index
– Upper limbs: 9 hole peg test (9HPT), Box and Block test, Functional dexterity test, Jebsen test, Sollerman hand function test, Shape texture identification test, DASH
– Global: ONLS, Barthel Index, Rankin scale
• Qol– SF36, RAND
136th ENMC Workshopon CMT1A
April 8-10, 2005
International panel of experts (clinicians, neuroepidemiologist, pharmacologist, basic
researchers). Agreement on outcome measures, trial design, etc.
168th ENMC WorkshopOutcome measures and clinical trials in CMT September 18-20, 2009Naarden
Recommended core outcome measures• CMT neuropathy score (CMTNS)
• Quantitative motor strength assessment
• VAS for pain and fatigue
• 10-meter timed walking
• Overall Neuropathy Limitations Scale (ONLS)
• SF-36
• Electrophysiology: Non-dominant side– CV of CMTNS nerves;
– motor nerves 2 upper limb, 1 lower limb (peroneal), (MCV, DL, CMAP); 1 sensory (ulnar, SAP ampl., SCV)
136th, 2005
MRC Centre for Neuromuscular Disease
N° patients recruited =
272
2 YEARS
Anglo-Italian study
CMT-TRIAAL &
CMT-TRAUK
MRC Centre for Neuromuscular Disease
Reliability study before
starting
SCREENINGgenetically confirmed,
symptomatic CMT1A patients
RANDOMIZATION
ASCORBIC ACID 1,5 g/day PLACEBO
6 MONTH FOLLOW-UP*
12 MONTH FOLLOW-UP
18 MONTH FOLLOW-UP
24 MONTH FOLLOW-UP
6 MONTH FOLLOW-UP
12 MONTH FOLLOW-UP
18 MONTH FOLLOW-UP
24 MONTH FOLLOW-UP
January 2006: FIRST PATIENT SCREENED
March 2006 - March 2007
December 2007INTERIM ANALYSIS
(March 2009 Italy, July 2009 UK)TRIAL CLOSURE, FINAL ANALYSIS
WE ARE HERE
Age: mean 42.54, SD 13.13, range 18-70 yrs.
CMT Neuropathy Score (CMTNS)
• Composite scale (Shy et al. Neurology 2005;64:1209)
• Symptoms– Sensory in legs only = 1– Motor arms and legs =2
• Signs– Sensory, vibration and pin = 2– Motor arms and legs = 2
• Electrophysiology– Motor and sensory amplitude ulnar or median
nerve =2
Score = 0-36
RELIABLE
CHANGE SENSITIVE (Shy, 2008)0.686 / year progression in CMT1A adults
2.8 ± 1.76.1 ± 2.65.3 ± 1.7
14.2 ± 4.7
CMT neuropathy score (CMTNS) Symptoms Signs ENG Total score
0-10 mild = 26%; 11-20 moderate = 65%; >20 severe = 9%
Trial with Ascorbic acid in CMT1A Italy-UK Basal assessment (n = 271 pts.)
CMTNS: mean ± SD
Males 13.3 ± 4.2
Females 14.7 ± 5.0
AGE (yrs): mean ± SD
39.6 ± 12.0
44.8 ± 10.0
♂ ♀
CMTNS
0,00
2,00
4,00
6,00
8,00
10,00
12,00
14,00
16,00
18,00
18-29 30-39 40-49 50-59 60-70
symptomssignsENGTotal
CMTNS & age in CMT1A (n = 271) CMT-TRIAAL / CMT-TRAUK
years
score
handgrip 3-point pinch Foot plantar flexion
Maximal Voluntary Isometric Contraction (MVIC) CMT-TRIAAL & CMT-TRAUK, basal assessment (n
= 271 CMT1A patients)
Foot dorsiflex
87.4 ± 42.3 66.3 ± 31.3 65.3 ± 53.3 100.7 ± 64.7
MEAN VALUE ± SD (Newton)
Reliability study
0,00
20,00
40,00
60,00
80,00
100,00
120,00
18-29 30-39 40-49 50-59 60-70
grippinchplantar flexdorsiflexion
Strength (myometer) & AGE in CMT1A (n = 271)
years
Score (N)
Activity limitation ( = Disability)• 10 meter timed walking quantitative mobility and leg
function performance test = 9.16 ± 5.2 sec
• 9-hole peg test (9-HPT) Time taken to place and remove all 9 pegs
– Dominant side = 23.6 ± 7.4 sec
– Non-dominant side = 25.3 ± 7.2 sec
ONLS
arm score 0-5+
leg score 0-7=
Total 0-12
Graham & Hughes JNNP 2006
01
02
03
04
0
Per
cen
t
0 1 2 3 4 5 6ONLS (Total Score)
1.44 ± 0.951.70 ± 0.683.14 ± 1.31
Overall Neuropathy Limitations Scale - ONLS Arm score Leg score Total score
Basal assessment: 271 CMT1A pts (AA trial)
0,00
5,00
10,00
15,00
20,00
25,00
30,00
18-29 30-39 40-49 50-59 60-70
ONLS9HPT10MTW
years
scoreDisability & AGE in CMT1A (n = 271) CMT-TRIAAL / CMT-TRAUK
VAS for pain3.68 ± 3.02 cm
4.87 ± 2.81 cmVAS for fatigue
271 CMT1A pts.
02
46
810
vasd
olor
e0
1 2
VAS for PAIN
♂ ♀
02
46
810
vasf
atica
01 2
VAS for FATIGUE
♂ ♀
0
10
20
30
40
50
60
70
80
90
PF RP BP GH EN SF RE MH
CMT Patients
Italian Norms
42,99 ± 10,9846,02 ± 11,50
SF-36 QoL questionnaire Physical Composite Score (PCS) Mental Composite Score (MCS)
PF is physical functioning, RP role-physical, BP bodily pain, GH general health, EN energy, SF social functioning, RE role-emotional, MH mental health. P values < 0.001 for all comparison except MH (P=0.80).
* * ** *
* *QoL lower in CMT
42.44 (21.79)41.19 (40.18)53.45 (26.71)52.13 (21.57)43.93 (21.63)64.01 (24.42)50.75 (44.05)64.07 (19.82)
68.20 (23.30)66.21 (38.33)67.97 (28.18)56.37 (22.52)55.53 (22.18)74.46 (24.58)70.21 (39.85)68.12 (20.74)
75.91 (18.93)72.02 (34.36)69.01 (23.48)61.39 (20.19)54.75 (18.40)76.93 (23.88)68.65 (38.84)68.68 (16.54)
SF36 PF* RP* BP* GH* EN SF* RE MH
27.65 (9.89)23.60 (5.11)20.25 (2.89)9HPT * (sec)
10.69 (4.67)9.54 (6.65)7.05 (2.89)T10MW * (sec)
4.16 (0.81)3.06 (1.06)2.09 (1.14)ONLS *
≥ 16 (93 pts)
12-15 (94 pts)
0-11 (84 pts)
VariableMean value (SD)
CMTNS tertiles
Skin biopsy
• Consenting patients Mi-Ge-Na,
baseline & end of study (n = 53)
• Glabrous skin (proximal falanx II
finger or V finger tip)
• Study: PMP22 mRNA expression
(RT-PCR)
• CMT-TRIAAL & CMT-TRAUK: largest series ever evaluated and followed according to a standardised protocol.
• CMTNS correlates with other disability & QoL outcome measures
• CMTNS & other outcome measures correlate with age
• No correlation of pain, fatigue, QoL (SF36) with age
• Next phase evaluate responsiveness of OM
Sensitivity to change (CMT1A)
• CMTNS: 0.686 / yr CMT1A (Shy 2008)
• MCV (m/s): No or minimal change over time, no correlation with clinical severity
• CMAP ampl (mV)– Median -0.141 / yr; ulnar -0.074 / yr (Shy);
but also controls’ CMAP decrease over a 5-year period (Verhamme, in press)
• Quality of life (SF36, RAND) does not worsen over years in CMT (adaptation?)
No effectMCV median nerve (10 m/s)
1 year2 g 11(12-25 yrs)
Dutch
resultsPrimary endpoint
DurationDosageNumberTrial
Underway2 years3 g50children
German
UnderwayCMTNS2 years1.5 g60Czech
UnderwayCMTNS 2 years4 g114Futility des.
US
Data analysis underway
CMTNS (1.5)2 years1.5 g272Italian UK
No effectCMTES
CMTNS (5)1 year1 g / 3 g1803 arms
French
No effect (5 outliers)
MCV median nerve (2.5 m/s)
1 year30 mg/Kg81 childrenAustralian
Poor tolerability)
tolerability2 years5 gopen label
12(Toth
F lat, CMAP ampl (median n); MVIC 3-point-pinch, foot dorsiflexion; INCAT SS; CMTNS; ODSS; ADLS; 9HPT; 50 m timed walking
Dutch
SECONDARY ENDPOINTSTrial
German
same as Italian-UKCzech
presented tomorrow by Richard LewisUS
MVIC handgrip, 3-point-pinch, foot dorsiflexion and plantar flexion; ONLS, 9HPT, T10MW, VAS pain fatigue; SF36; electrophysiology, skin biopsy; AA assay; pain
Italian UK
QMT handgrip, foot dorsiflexion; ODSS; T10MW; VAS; GCI-S; SF36. AA assay
French
FPI; MVIC HHD; Bruininks-Oseretsky test Functional Motor Proficiency; Functional Power and endurance; Walking ability (GAITRite)
Australian
CMTNS, CSS, Rankin, AI, electrophysiology (4 motor & 5 sensory nerves)Toth
CURRENT EVIDENCE• 3 RCT finished
• >280 pts (about 190 treated) = None of endpoints reached
• Some post-hoc analysis results possibly indicate some efficacy (5 pts. in Australian, CMTES in French trial)
• 1 large trial just finished (272), 3 underway (about 220) Total of about 770 pts (450 treated pts, ITT)
• Different dosages explored, interesting to compare
Perspectives
• Meta-analysis (prospective)• Biomarkers (skin biopsy)• Lessons from these trials for the future
– Adequate powering & duration– Adequate primary outcome measure– CMTNS to be improved– ONLS not sensitive to change– MCV not good as primary outcome measure– Outcome measures for children
MRI
SKIN BIOPSY
Po
wer
[W/kg]
Hip Knee Ankle
Mo
men
t [Nm/kg]
An
gle
[°]
flex
ext
ext
flex
prod
abs
Gait Analysis
CMT-TRIAAL & CMT-TRAUK Groups
Investigators — “C. Besta” National Neurological Institute, Milan: D. Pareyson, E. Salsano, V. Scaioli, C. Ciano, M. Rimoldi, G. Lauria, E. Rizzetto, F. Camozzi; Department of Neurology, Ophthalmology and Genetics, University of Genoa: A. Schenone, M. Grandis, E. Narciso; Department of Neurological and Visual Sciences, Section of Clinical Neurology, University of Verona: N. Rizzuto, G.M. Fabrizi, T. Cavallaro; Department of Neurological Sciences, Federico II University of Naples: L. Santoro, F. Manganelli, M. Nolano; Sacro Cuore Catholic University, Rome: L. Padua, C. Pazzaglia; Department of Medical Sciences, "Magna Graecia" University of Catanzaro: A. Quattrone, P. Valentino; Department of Neurosciences, of Psychiatric and Anesthesiologic Sciences, Messina University: G.Vita, A. Mazzeo, M. Aguenoz; Department of Neuroscience, University of Parma: F. Gemignani, F. Brindani,
MRC Centre for Neuromuscular Disease
9 gastrointestinal disturbances1 gum disease 4 pregnancies2 foot surgery 1 lumbar spine surgery 1 renal stones1 saccharine intolerance
13 retired consent
Drop outs = 32 (11.8%)
Sample size
• Assumption of: improvement ≥ 0.5 in the CMTNS in participants assigned to AA, versus 1 point worsening in the placebo arm at 24 months since enrolment
• 90% power, level of significance of 5% (two-tailed) = 113 participants per group to detect the above difference
• postulated values of the means (standard deviations) at two years = 13.0 (6.5) for the AA group, 14.5 (6.5) for the placebo group
• Assuming an attrition of 20%, at least 272 participants (136 / group) enrolled in 12 months
INCLUSION CRITERIA:
1. Clinical diagnosis of CMT1A
2. Genetic confirmation (17p11.2 duplication)
3. CMT Neuropathy Score between 1 (excluding the electrophysiologicalcomponent) and 35 (including the electrophysiological component)
4. Age 18-70 years
5. Ability to accomplish the primary outcome measures
6. Women of child-bearing age only if they declare not to be pregnant or breastfeeding at the inclusion into the study and to avoid becoming pregnant during thestudy
7. Signed informed patient consent
EXCLUSION CRITERIA:
1. Clinical or echographic diagnosis of nephrolithiasis
2. Positive history of recurrent renal colics
3. One or more episodes of renal colic in the 6 months prior to screening
4. Deficit of Glucose-6P-Dehydrogenase
5. Acquired or hereditary haemochromatosis; thalassemia major; syderoblasticanaemia
6. Treatment with potential therapeutic agents for CMT1A in the three months priorto screening
7. AA consumption in the three months prior to screening
8. Other causes of neuropathy
9. Other neurological disorders, or major comorbidities
10. Limb surgery in the six months prior to screening, or planned before finalassessment
Electrophysiology
• 3 motor nerves
– (ulnar, median, peroneal)
• 1 sensory nerve (ulnar)
Ulnar, Median
PeronealCMAP, MCV, DL (fixed distance)SCV, SAP amplorthodromic
Non-dominant side
Paraclinical OM• NERVE CONDUCTION VELOCITIES• CMAP AMPLITUDE• SAP AMPLITUDE• MUNE Motor Unit Number Estimation• QST Quantitative Sensory Testing• MRI• ULTRASOUNDS• GAIT ANALYSIS• BIOMARKERS - SKIN BIOPSY
• NIS Neuropathy Impairment Score (weakness, DTRs, sensory loss)– 1 point/year progression in 31 CMT1 patients
(Dyck 1989) – 1.386 / year progression in CMT1A adults (Shy 2008)
• CMAP (& SAP) amplitudes: correlation with impairment and disability – Axonal loss as basis of disability and disease
progression– MCV no correlation with severity in CMT1A
• Padua 2008, Teunissen 2003:– Progression in CMT1A and CMT2 – Quality of life does not worsen over years
Electrophysiology (MCV, DL, CMAP ampl, SAP ampl, MUNE)
• Change with age (CMT1A):– DL first to change– MCV change after 6 yrs– Change little over years
• Dyck 1989 CMT1• Killian 1996 CMT1A -2.2 (ulnar) and -3.0 (peroneal) m/s over
22 years• Shy 2008 CMT1A median nerve MCV -0.6 m/s/year; ulnar
nerve 0.0 m/s/year• CMT1A do not correlate with severity; lower MCV worse
prognosis (Birouk 1997, Verhamme 2004)– CMAP
• Correlate with disease severity (disability) Krajewski 2000• (not according to Birouk 1997 and Hoogendijik 1994)
– MUNE• Correlation with disability in the hand (Videler, Neurology
2008)
OM validated in CMT: Solari et al. 2008 • Good to excellent intra & inter-examiner
reliability in 40 CMT pts of the following OM:– MVIC quantitative strength assessment
(hand-held myometer)– Overall Neuropathy Limitations Scale– 10-meter timed walking– 9 hole peg test
Walk-12
Activity limitations
Self-administered questionnaire
Physical Functioning Role limitation, Phys.Bodily PainGeneral Health
Vitality (Energy)Role limitation, Emot.Social FunctioningMental Health
Physical HealthComposite
Mental HealthComposite
SF-36
QUALITY OF LIFE
Choice of the target population
• Age: Adults – children? Elderly?• Diagnosis: clinical - molecular diagnosis?• Disease severity: asymptomatic pts?
CMTNS: CMT-NE >0 / CMTNS <35 • Exclusion criteria:
– Other causes of neuropathies– Other neurological disorders or major
comorbidities– Other trials (less than 6 months?)– Pregnancy – breast feeding
• Contraindications to specific drugs
3.83 ± 0.993.80 ± 0.97ABDUCTOR POLLICIS BREVIS(mean SD)
3.73 ± 0.953.72 ± 0.87I INTEROSSEOUS(mean SD)
NON- DOMINANT
HAND
DOMINANT HAND
(R 94%)
Manual testing MRC score(271 pts.)
Overwork weakness?
CMT-TRIAAL & CMT-TRAUK Groups
Investigators — “C. Besta” National Neurological Institute, Milan: D. Pareyson, E. Salsano, V. Scaioli, C. Ciano, M. Rimoldi, G. Lauria, E. Rizzetto, F. Camozzi; Department of Neurology, Ophthalmology and Genetics, University of Genoa: A. Schenone, M. Grandis, E. Narciso; Department of Neurological and Visual Sciences, Section of Clinical Neurology, University of Verona: N. Rizzuto, G.M. Fabrizi, T. Cavallaro; Department of Neurological Sciences, Federico II University of Naples: L. Santoro, F. Manganelli, M. Nolano; Sacro Cuore Catholic University, Rome: L. Padua, C. Pazzaglia; Department of Medical Sciences, "Magna Graecia" University of Catanzaro: A. Quattrone, P. Valentino; Department of Neurosciences, of Psychiatric and Anesthesiologic Sciences, Messina University: G.Vita, A. Mazzeo, M. Aguenoz; Department of Neuroscience, University of Parma: F. Gemignani, F. Brindani,
MRC Centre for Neuromuscular Disease
